Fragment-Based Drug Design: Computational and Experimental State of the Art

Hoffer, Laurent; Renaud, Jean‐Paul; Horvath, Dragos

doi:10.2174/138620711795767884

Cited by 42 publications

(44 citation statements)

References 152 publications

(177 reference statements)

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“…The following paragraphs give an overview of these screening technologies. However, for a more thorough understanding of these fragment screening methodologies, the reader is referred to other in-depth reviews describing the advantages and disadvantages, which have been published in recent years [15,21,[44][45][46].…”

Section: Identification Of Fragment Hitmentioning

confidence: 99%

“…Other groups also used high concentration biochemical screening as their primary fragment screening approach to identify inhibitors of phosphatidylinositol-3 kinase [88], phosphoinositide-dependent kinase-1 (PDK1) [89] and betasecretase (BACE-1) [90]. Nowadays, with significant successes of using high concentration screening by biological assays reported, many groups in pharmaceutical industry are using fragments in HTS screening at higher concentration to develop target focused sets of fragments for further biophysical screening [15].…”

Section: Biochemical Assays/high Concentration Screeningsmentioning

confidence: 99%

“…A large number of successful examples of using growing approach for fragment optimization have been reported in literature. We cannot cover all of these studies and a number of recently published reviews can be consulted [10,13,15,21,101,102]. Recent studies that utilized fragment growing as an optimization strategy include the discovery of Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) [70], Acetylcholine-binding protein (AChBP) [103], Matrix metalloproteinases (MMPs) [104] and phosphatidylinositol-3 kinases (PI3Ks) [88] inhibitors.…”

Section: Fragment Growingmentioning

confidence: 99%

“…The optimization of fragments is an iterative process where the potency of the initial fragment is improved in each step by adding functional groups, or linking two independent fragments together. FBDD is hallmarked by three advantages compared with a conventional HTS drug discovery approach [10,15]. The first advantage is that the chemical diversity space is better covered with FBDD.…”

Section: Introductionmentioning

confidence: 99%

“…Large molecules, on the other hand, contain more functional groups that may present more steric hindrance or electrostatic clashes than the fragment molecule in a binding site. These molecular incompatibilities prevent most large molecules from being accommodated in the protein pockets [15,19]. Finally, the third advantage is that compounds optimized from fragments exhibit high binding efficiency per atom as compared to compounds optimized from HTS.…”

Section: Introductionmentioning

confidence: 99%

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Fragment Based Drug Design: From Experimental to Computational Approaches

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Fragment based drug design has emerged as an effective alternative to high throughput screening for the identification of lead compounds in drug discovery in the past fifteen years. Fragment based screening and optimization methods have achieved credible success in many drug discovery projects with one approved drug and many more compounds in clinical trials. The fragment based drug design starts with the identification of fragments or low molecular weight compounds that generally bind with weak affinity to the target of interest. The fragments that form high quality interactions are then optimized to lead compounds with high affinity and selectivity. The weak affinity of fragments for their target requires the use of biophysical techniques such as nuclear magnetic resonance, X-ray crystallography or surface plasmon resonance to identify hits. These techniques are very sensitive and some of them provide detailed protein fragment interaction information that is important for fragment to lead optimization. Despite the huge advances in technology in the past years, experimental methods of fragment screening suffer several challenges such as low throughput, high cost of instruments and experiments, high protein and fragment concentration requirements. To address challenges posed by experimental screening approaches, computational methods were developed that play an important role in fragment library design, fragment screening and optimization of initial fragment hits. The computational approaches of fragment screening and optimization are most useful when they are used in combination with experimental approaches. The use of virtual fragment based screening in combination with experimental methods has fostered the application of fragment based drug design to important biological targets including protein-protein interactions and membrane proteins such as GPCRs. This review provides an overview of experimental and computational screening approaches used in fragment based drug discovery with an emphasis on recent successes achieved in discovering potent lead molecules using these approaches.

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